Study may point way to AIDS cure; new combined therapy helps remove dormant HIV in immune system cells

CHAPEL HILL - A drug known for its anti-seizure and antidepressant activity appears to be the key ingredient in a new combination therapy that may direct scientists to an AIDS cure.

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Aug. 11, 2005

Study may point way to AIDS cure; new combined therapy helps remove dormant HIV in immune system cells

By LESLIE H. LANGUNC School of Medicine

CHAPEL HILL - A drug known for its anti-seizure and antidepressant activity appears to be the key ingredient in a new combination therapy that may direct scientists to an AIDS cure.

The new research is reported in the Saturday (Aug. 13) issue of The Lancet, the international medical journal based in England. The study shows for the first time that the drug valproate (valproic acid), in combination with an intensified version of the standard AIDS drug cocktail known as HAART, or highly active anti-retroviral therapy, might eradicate dormant HIV viruses from their hiding place in resting immune system cells.

“Studies have shown that persistent infection in a reservoir of resting, or quiescent, CD4+ T cells prevents viral eradication by HAART,” said Dr. David M. Margolis, the study’s senior author and professor of medicine, microbiology and immunology in the School of Medicine and professor of epidemiology in the School of Public Health at the University of North Carolina at Chapel Hill.

“Our findings suggest a new and practical approach to eliminate HIV infection in this persistent reservoir.”

CD4+ T cells are white blood cells that orchestrate the immune response, signaling other cells in the immune system to perform their special functions. Also known as helper T cells, these cells are killed or disabled during HIV infection.

Prior to joining the UNC faculty this month, Margolis and his laboratory at the University of Texas Southwestern Medical Center at Dallas for several years explored how HIV can lay silent or dormant in resting T cells, an issue Margolis called a major conceptual barrier to the eradication of HIV infection.

Added Margolis, “There are shortcomings to current anti-retroviral therapy; currently it works 99.99 percent but that last .01 percent is still a problem. There remains low-level viral replication that goes on despite current therapy.

“But even if we could overcome that last one-hundredth of a percent of replication, there is no way that the dormant latent virus can be cleared by the immune system or by current anti-viral therapy. There has been no approach that specifically attacks this reservoir of infection.”

Among the key host enzymes that help maintain HIV’s latency is histone deacetylase 1 (HDAC1), part of the “off” switch in gene expression, Margolis said. Several years of research in his laboratory led to the finding that a class of drugs developed for other medical reasons is targeting the enzyme. Valproate, or valproic acid, is one of these drugs.

The next step was to conduct a clinical study involving HIV-infected individuals, one that might offer “proof of concept” that tested the ability of valproate to deplete persistent, latent infection in resting CD4+ T cells.

“We were attempting to prove that the biochemical mechanism of action that we had already shown in various human cell culture systems in the lab could also work in humans given a clinically safe dose of valproate,” Margolis said.

In the study, four adult volunteers infected with HIV and on treatment with HAART also received injections of the drug enfuvirtide twice daily for six weeks. Oral doses of valproate twice daily were then added to the treatment regimen for three months. Laboratory assays measured latent infection of CD4+ T cells before and after intensified treatment with valproate.

“Instead of having to develop a drug from scratch, we were able to go to the hospital pharmacy and write prescriptions for valproate, which is a drug that’s used to prevent seizures and now to treat depression. And it’s a drug that inhibits the very same enzyme that’s key for the viral latency,” Margolis said.

During the study, the Dallas team collected billions of CD4+ cells from the volunteers’ blood samples and isolated hundreds of millions of resting CD4+ T cells.

The study showed a 75 percent average decline in latent infection, with a range between 68 percent and more than 84 percent.

“Further studies are needed to confirm, expand and deepen our observations,” the study said. Additionally, the findings, though not definitive, suggest that new approaches will allow the cure of HIV in the future.

“For the last few years investigators have been meeting quietly to discuss the challenge of ‘the latent pool.’ Indeed, it is this ‘special HIV compartment’ that has blocked investigators even from so much as openly talking about a cure for HIV and AIDS,” he said.

“Dr. David Margolis’ work is the first bright light at the end of a very long tunnel. He has shown, at least preliminarily, that it is feasible to attack the latent pool. I would hope that this report would galvanize research teams to pursue this critical goal.”

Along with the University of Texas Southwestern Medical Center at Dallas team were co-authors from the National Cancer Institute; Rush-Presbyterian-St. Luke’s Medical Center; the University of California at San Diego and Veterans Affairs Medical Center, San Diego; the University of Washington; the University of Pittsburgh School of Medicine; the Harvard School of Public Health; and North Texas Veterans Health Care Systems in Dallas.

The National Institutes of Health and the Veterans Affairs Research Service supported the research.